genetic variant at the fatty acid-binding protein aP2 locus reduces the risk for hypertriglyceridemia, type 2 diabetes, and cardiovascular disease

• Published in: Proceedings of the National Academy of Sciences - PNAS 2006-05, Vol.103 (18), p.6970-6975
• Main Authors: Tuncman, G, Erbay, E, Hom, X, De Vivo, I, Campos, H, Rimm, E.B, Hotamisligil, G.S
• Format: Article
• Language: English
• Subjects: adipose tissue; Adipose Tissue - physiology; Adipose tissues; Adult; Alleles; Animals; aP2 gene; aP2 locus; Base Sequence; binding capacity; Biological Sciences; cardiovascular diseases; Cardiovascular Diseases - genetics; CCAAT-Enhancer-Binding Protein-alpha - metabolism; Cellular biology; Cohort Studies; Diabetes Mellitus, Type 2 - genetics; DNA; fatty acid-binding proteins; Fatty Acid-Binding Proteins - chemistry; Fatty Acid-Binding Proteins - genetics; Fatty Acid-Binding Proteins - metabolism; Fatty acids; Female; gene expression; gene frequency; genes; Genetic Predisposition to Disease; genetic variation; Genotype; Genotype & phenotype; Human genetics; Humans; hypertriglyceridemia; Hypertriglyceridemia - genetics; Lipid metabolism; loci; Medical genetics; Metabolic diseases; Metabolic syndrome; Middle Aged; Molecular Sequence Data; noninsulin-dependent diabetes mellitus; Obesity; Obesity - complications; Obesity - epidemiology; Obesity - genetics; Odds Ratio; Phenotype; Polymorphism, Genetic; Population genetics; Promoter regions; Promoter Regions, Genetic; Prospective Studies; Protein Binding; Protein Isoforms - genetics; Protein Isoforms - metabolism; Proteins; single nucleotide polymorphism; transcription factors; Transcription, Genetic; Triglycerides - blood; Type 2 diabetes mellitus
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0602178103

Obesity and the associated pathologies including dyslipidemia, insulin resistance, type 2 diabetes, and cardiovascular disease constitute a major threat to global human health. Yet, the genetic factors that differentially predispose individuals to this cluster of pathologies are unclear. The fatty acid-binding protein aP2 is a cytoplasmic lipid chaperon expressed in adipocytes and macrophages. Mice with aP2 deficiency are partially resistant to obesity-induced insulin resistance and type 2 diabetes, have lower circulating triglycerides, and exhibit marked protection against atherosclerosis. Here, we demonstrate a functionally significant genetic variation at the aP2 locus in humans that results in decreased adipose tissue aP2 expression due to alteration of the CAAT box/enhancer-binding protein binding and reduced transcriptional activity of the aP2 promoter. In population genetic studies with 7,899 participants, individuals that carry this T-87C polymorphism had lower serum triglyceride levels and significantly reduced risk for coronary heart disease and type 2 diabetes compared with subjects homozygous for the WT allele. Taken together, our results indicate that reduction in aP2 activity in humans generate a metabolically favorable phenotype that is similar to aP2 deficiency in experimental models.